The many synonyms for tick-borne encephalitis (TBE) chart the history of this important tick-borne viral disease. Many viruses isolated from ticks collected across Europe, Asia, and North America have been shown to be antigenically related to the virus species, Tick-borne encephalitis virus (TBEV). The life cycle of TBEV can be represented by a triangle of parasitic interactions. The interactions are between (i) virus-tick, (ii) virus-host, and (iii) tick-host. In virus-tick interactions, TBEV interacts with its tick vector, infecting and replicating within tick cells including those of the gut, hemocoel, and salivary glands. The goal of the virus is to infect the tick’s salivary glands so that it can be transmitted in saliva when the infected tick feeds. The ability of a particular tick species to act as a vector depends on whether TBEV can survive and overcome several barriers within the tick, e.g., the environment within the midgut where the virus is initially taken up in the blood meal, the gut infection barrier, and the salivary gland infection barrier. This chapter discusses summary of epidemiology and map of distribution of TBEV. Then, it presents clinical manifestations, diagnosis, treatment, and preventive measure of TBE.